Increased insulin sensitivity in paternal Gnas knockout mice is associated with increased lipid clearance

Endocrinology. 2004 Sep;145(9):4094-102. doi: 10.1210/en.2004-0038. Epub 2004 May 27.

Abstract

The G protein alpha-subunit Gsalpha is required for hormone-stimulated cAMP generation. The Gsalpha gene Gnas is a complex gene with multiple imprinted gene products. Mice with heterozygous disruption of the Gnas paternal allele (+/p-) are partially Gsalpha deficient and totally deficient in XLalphas, a neuroendocrine-specific Gsalpha isoform that is expressed only from the paternal Gnas allele. We previously showed that these mice are hypermetabolic and lean and have increased insulin sensitivity. We now performed hyperinsulinemic-euglycemic clamp studies, which confirmed the markedly increased whole body insulin sensitivity in +/p- mice. +/p- mice had 1.4-, 7- and 3.8-fold increases in insulin-stimulated glucose uptake in muscle and white and brown adipose tissue, respectively, and markedly suppressed endogenous glucose production from the liver. This was associated with increased phosphorylation of insulin receptor and a downstream effector (Akt kinase) in both liver and muscle in response to insulin. Triglycerides cleared more rapidly in +/p- mice after a bolus administered by gavage. This was associated with decreased liver and muscle triglyceride content and increased muscle acyl-CoA oxidase mRNA expression. Resistin and adiponectin were overexpressed in white adipose tissue of +/p- mice, although there was no difference in serum adiponectin levels. The lean phenotype and increased insulin sensitivity observed in +/p- mice is likely a consequence of increased lipid oxidation in muscle and possibly other tissues. Further studies will clarify whether XLalphas deficiency is responsible for these effects and if so, the mechanism by which XLalphas deficiency leads to this metabolic phenotype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adiponectin
  • Adipose Tissue / metabolism
  • Animals
  • Chromogranins
  • GTP-Binding Protein alpha Subunits, Gs / genetics*
  • Gene Expression
  • Hormones, Ectopic / genetics
  • Hypoglycemic Agents / metabolism*
  • Hypoglycemic Agents / pharmacology
  • Insulin / metabolism*
  • Insulin / pharmacology
  • Intercellular Signaling Peptides and Proteins*
  • Liver / metabolism
  • Mice
  • Mice, Inbred Strains
  • Mice, Knockout
  • Muscle, Skeletal / metabolism
  • Phenotype
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism
  • Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Receptor, Insulin / metabolism
  • Resistin
  • Sympathetic Nervous System / physiology
  • Triglycerides / metabolism*

Substances

  • Adiponectin
  • Chromogranins
  • Hormones, Ectopic
  • Hypoglycemic Agents
  • Insulin
  • Intercellular Signaling Peptides and Proteins
  • Proteins
  • Proto-Oncogene Proteins
  • Resistin
  • Retn protein, mouse
  • Triglycerides
  • Receptor, Insulin
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Gnas protein, mouse
  • GTP-Binding Protein alpha Subunits, Gs